Polycystic Ovary Syndrome 1

Clinical Features

Stein and Leventhal (1935) demonstrated that obesity, hirsutism, and amenorrhea are clinical correlates of enlarged polycystic ovaries. Thereafter, the criteria were established as bilateral enlarged ovaries, normal 24-hour urinary ketosteroids, and lack of virilization. Response to ovarian wedge resection was included as a criterion by some. The fathers tend to be abnormally hairy, female sibs are hirsute, and mothers and sisters often have oligomenorrhea. Culdoscopy has often shown signs of Stein-Leventhal syndrome, e.g., 8 of 12 sisters of cases showed ovarian changes consistent with that diagnosis (Cooper et al., 1968). Urinary steroid determinations also suggest a genetic basis.

Ovarian hyperthecosis was the term used by Givens et al. (1971), who found 41 women (in 2 kindreds) who had hirsutism and/or oligomenorrhea. Ovarian histology performed in 8 showed hyperplasia of theca cells in atretic follicles, a paucity of primordial and developing follicles, and stromal hyperplasia. Elevated levels of androstanedione and/or testosterone and of luteinizing hormone were found. Estradiol and follicle-stimulating hormone levels were low. These levels tended to return to normal after bilateral wedge resection of the ovaries. Some men of the families had low plasma testosterone and had abnormally high LH-FSH ratio as in the women. The pedigrees were consistent with dominant inheritance, probably autosomal because in 1 kindred the disorder was apparently transmitted through a father and son.

Mandel et al. (1983) studied 4 families, each with 2 affected sisters; in 1 family, the mother and a maternal aunt were likewise affected. The diagnosis of PCO was confirmed by increased serum testosterone, androstenedione, and LH levels compared to those in normal women. Elevated concentrations of dehydroepiandrosterone sulfate indicated excess adrenal androgen secretion.

Kuttenn et al. (1985) concluded that their 24 hirsute women with late-onset adrenal hyperplasia due to 21-hydroxylase deficiency (201910) were indistinguishable from those with idiopathic hirsutism or Stein-Leventhal syndrome. Chrousos et al. (1982) made the same observation. Stein-Leventhal syndrome is probably heterogeneous; see 264300 for information that some patients may have deficiency of estradiol 17-beta-dehydrogenase. It appears that 'idiopathic hirsutism,' which at times is familial, is sometimes due to increased skin sensitivity to androgen and occurs in the absence of elevated plasma androgens (Kuttenn et al., 1977). On the basis of a large family study, Hague et al. (1986) arrived at an hypothesis of dominant inheritance with meiotic drive accounting for the anomalous segregation. They found PCO in 96% of daughters of affected females and in 82% of daughters of carrier males.

Lunde et al. (1989) reported that 19.7% of male first-degree relatives of PCO patients had early baldness or excessive hairiness, as opposed to 6.5% of relatives of controls. For female first-degree relatives, the percentages for PCO-related symptoms were 31.4 and 3.2, respectively. In a subgroup of 52 families of PCO patients in which 1 of the parents was reported to have symptoms, 35% of brothers and 58% of sisters had symptoms. The findings were considered consistent with autosomal dominant inheritance for a 'sizeable fraction of families.' The possibility of X-linked dominant inheritance was eliminated.

Franks et al. (1997) favored an oligogenic basis (over autosomal dominant inheritance) for polycystic ovary syndrome. They stated that it is the most common endocrinopathy in women of reproductive age.

In preliminary family studies, Legro et al. (1998) found that some female first-degree relatives of women with PCO syndrome have hyperandrogenemia. They hypothesized that this may be a genetic trait suitable for linkage analysis. They examined 115 sisters of 80 probands with PCO syndrome from unrelated families. PCO syndrome was diagnosed by the combination of elevated serum androgen levels and 6 or fewer menses per year with the exclusion of secondary causes. The diagnostic criteria for PCO syndrome were fulfilled in 22% of the sisters. In addition, 24% of the sisters had hyperandrogenemia and regular menstrual cycles. Probands, sisters with PCO syndrome, and hyperandrogenemic sisters had elevated serum luteinizing hormone levels compared with control women. The familial aggregation of hyperandrogenemia in PCO syndrome kindreds suggested that it is a genetic trait which can be used to assign affected status in linkage studies designed to identify PCO syndrome genes.

Polycystic ovary syndrome is associated with an increased risk of type II diabetes mellitus. Defects in both insulin action and insulin secretion contribute to this predisposition to diabetes. Colilla et al. (2001) used the frequently sampled intravenous glucose tolerance test to quantitate insulin secretion, insulin action, and their product among 33 women with PCOS and 48 nondiabetic first-degree relatives. They then quantitated the heritability of these measures from familial correlations estimated within a genetic model. The sib correlation for insulin secretion was highly significant. In addition, the parameter quantitating insulin secretion in relation to insulin sensitivity was significant among sibs. The authors concluded that there is a heritable component to beta-cell dysfunction in families of women with PCOS, and that heritability of beta-cell dysfunction is likely to be a significant factor in the predisposition to diabetes in PCOS.

Ehrmann et al. (2005) examined the effects of race and family history of type II diabetes on the risk of impaired glucose tolerance (IGT) and type II diabetes in a large cohort of women with PCOS. They found that a family history of type II diabetes in a first-degree relative was associated with an increased risk of metabolic abnormality, IGT, and type II diabetes in women with PCOS. They also observed higher insulin levels and greater insulin resistance in black women with PCOS than in white women with PCOS; these differences remained statistically significant even after taking the family history of diabetes into account.

The menstrual disturbances, androgen excess, and obesity that characterize PCOS suggest that women with PCOS may be at increased risk for obstructive sleep apnea. Fogel et al. (2001) observed by overnight polysomnography that women with PCOS had a higher apnea-hypopnea index than controls. The authors concluded that women with PCOS were more likely to suffer from symptomatic obstructive sleep apnea syndrome. Furthermore, apnea-hypopnea index correlated with waist-hip ratio, serum testosterone, and unbound testosterone in women with PCOS.

Bonini et al. (2007) performed a complete eye examination on 20 of 62 consecutive patients with PCO with or without hyperandrogenism who had a history of ocular symptoms. Women with PCOS were more likely to have itchy-dry eyes, decreased tear break-up time, and increased conjunctival goblet cell density compared with both PCO patients and healthy subjects.

Sir-Petermann et al. (2007) studied adiponectin serum concentrations and metabolic parameters in prepubertal and pubertal daughters of women with PCOS to identify girls with increased metabolic risk. Fifty-three prepubertal and 22 pubertal daughters of PCOS women and 32 prepubertal and 17 pubertal daughters of control women were studied. Both groups had similar chronological ages, body mass index SD score, and Tanner stage distribution. In the prepubertal girls, 2-hour insulin was higher and adiponectin levels were lower in the PCOS daughter group compared with the control daughter group. In the pubertal girls, triglycerides, 2-hour insulin, and serum testosterone concentrations were higher, and SHBG (182205) lower, in PCOS daughters compared with control daughters, but adiponectin (605441) levels were similar in both groups. Sir-Petermann et al. (2007) concluded that some of the metabolic features of PCOS are present in daughters of PCOS women before the onset of hyperandrogenism. Adiponectin appears to be one of the early markers of metabolic derangement in these girls.

Polycystic Ovary Syndrome Associated with Male Pattern Baldness

Carey et al. (1993) described an autosomal dominant syndrome of polycystic ovaries and premature male pattern baldness (109200). Carey et al. (1994) demonstrated an association with a change in the 5-prime promoter region of the CYP17 gene (609300), which modified the expression of the syndrome in some families but did not appear to be the primary genetic defect.

Govind et al. (1999) screened first-degree relatives of women affected by PCO to obtain evidence for the genetic basis of polycystic ovaries and premature male pattern baldness (PMPB). Of the relatives of 29 PCO probands, 15 of 29 (52%) mothers, 6 of 28 (21%) fathers, 35 of 53 (66%) sisters, and 4 of 18 (22%) brothers were assigned affected status. First-degree female and male relatives of affected individuals had a 61% and 22% chance of being affected, respectively. Of all sibs of PCO probands, 39 of 71 were affected, giving a segregation ratio of 39/32 (55%), which is consistent with autosomal dominant inheritance for PCO/PMPB. Thus the inheritance of PCO and PMPB is consistent with an autosomal dominant mode in PCO families. Sisters of PCO probands with polycystic ovarian morphology were more likely to have menstrual irregularity and had larger ovaries and higher serum androstenedione and dehydroepiandrosterone sulfate levels than sisters without PCO, suggesting a spectrum of clinical phenotypes in PCO families. Men with PMPB had higher serum testosterone than those without. The authors concluded that these data are consistent with a role for genetic differences in androgen synthesis, metabolism, or action in the pathogenesis of PCO.

Polycystic ovary syndrome is the most common form of female infertility in the U.S. In addition to poor conception rates, pregnancy loss rates are high (30-50%) during the first trimester. Jakubowicz et al. (2002) hypothesized that hyperinsulinemic insulin resistance contributes to early pregnancy loss in the syndrome, and that decreasing hyperinsulinemic insulin resistance with metformin during pregnancy would reduce the rate of early pregnancy loss. They conducted a retrospective study of all women with polycystic ovary syndrome who were seen in an academic endocrinology clinic within the past 4.5 years and who became pregnant during that time. Sixty-five women received metformin during pregnancy (metformin group) and 31 women did not (control group). The early pregnancy loss rate in the metformin group was 8.8%, as compared with 41.9% in the control group (P less than 0.001). In the subset of women in each group with a prior history of miscarriage, the early pregnancy loss rate was 11.1% in the metformin group, as compared with 58.3% in the control group (P equal to 0.002). The authors concluded metformin administration during pregnancy reduces first trimester pregnancy loss in women with polycystic ovary syndrome.

Harborne et al. (2003) demonstrated that metformin is potentially an effective treatment for moderate to severe hirsutism in women with PCOS, in some respects more efficacious than the standard treatment (Dianette). The data suggested that hirsutism may be effectively treated by reducing hyperinsulinemia.

Zumoff et al. (1983) presented evidence for a chronobiologic abnormality in secretion of luteinizing hormone. Whether the abnormality resides in the hypothalamus or pituitary was not clear.

The pathogenesis of polycystic ovary syndrome was discussed by McKenna (1988) and Givens (1988).

Stewart et al. (1990) presented evidence suggesting that the fundamental defect in many cases of PCO disease is increased 5-alpha-reductase activity in the liver and skin. As a result, testosterone is converted to the more potent androgen dihydrotestosterone, leading to hirsutism.

To assess the potential contribution of leptin (164160) to the pathogenesis of PCO, Mantzoros et al. (1997) measured leptin levels in obese women with PCO and in controls to determine if alterations in hyperinsulinemia produced by administration of the insulin-sensitizing agent troglitazone had an effect on serum leptin levels. Baseline leptin levels were not different between PCO and control subjects and remained unchanged after treatment with troglitazone. They concluded that leptin levels in patients with PCO do not differ from those in controls and that increased circulating insulin due to insulin resistance does not appear to alter circulating leptin levels in women with PCO.

Jakimiuk et al. (1999) sought to determine if there is increased SRD5A activity or mRNA expression in polycystic ovaries. SRD5A1 (184753) and SRD5A2 (607306) mRNAs were measured in thecal (TC) and granulosa (GC) cells from individual follicles of 18 women with PCOS and 26 regularly cycling control women. SRD5A1 and SRD5A2 mRNA expression was higher in GC than in TC, and SRD5A2 mRNA levels were approximately 3-fold higher than SRD5A1 mRNA. SRD5A1 and SRD5A2 mRNA expression was similar in GC from PCOS and control women, but SRD5A mRNA was decreased in TC from PCOS follicles. The total SRD5A activity was approximately 4-fold higher in PCOS follicles than in control follicles. These data demonstrated elevated SRD5A activity in polycystic ovaries and supported the hypothesis that 5-alpha-reduced androgens may play a role in the pathogenesis of PCOS.

CYP17 (609300) expression in propagated theca cells isolated from the ovaries of women with PCO is persistently elevated, compared with theca cells isolated from normal ovaries. To investigate the mechanism for increased CYP17 mRNA accumulation in PCO theca cells, Wickenheisser et al. (2000) examined CYP17 and steroidogenic acute regulatory protein (StAR; 600617) promoter activities in normal and PCO theca cells. Basal and forskolin-stimulated CYP17 promoter activity was 4-fold greater in PCO cells than in theca cells isolated from normal ovaries. The authors concluded from these data that (1) basal and cAMP-dependent CYP17 gene transcription is increased in PCO theca cells; (2) there is differential regulation of promoters of genes required for steroidogenesis in PCO theca cells; and (3) passaged normal and PCO theca cells provide a model system for studying tissue-specific regulation of genes encoding steroidogenic enzymes and identifying the molecular mechanisms involved in increased androgen production in PCO.

To investigate the role of X chromosome inactivation (XCI) on the clinical presentation of PCOS, Hickey et al. (2006) examined patterns of between sister pairs with the same genotype at a polymorphic locus on the X chromosome in families with PCOS. PCOS was defined as hyperandrogenemia with chronic anovulation. The statistical odds on a different clinical presentation between sisters was approximately 29 times higher in sister pairs with different patterns of XCI, compared with sister pairs with the same pattern of XCI (odds ratio 28.9; 95% confidence interval 4.0-206; P = 0.0008). They concluded that their study provided evidence to support a closer inspection of X-linked genes in PCOS, one in which both genotype and epigenotype are considered.

Estimates of the prevalence of PCO in the general population have ranged from 2 to 20%. The vast majority of these reports have studied white populations in Europe, used limited definitions of the disorder, and/or used bias populations, such as those seeking medical care. To estimate the prevalence of this disorder in the U.S. and address these limitations, Knochenhauer et al. (1998) prospectively determined the prevalence of PCO in a reproductive-aged population of 369 consecutive women (174 white and 195 black; aged 18 to 45 years) examined at the time of their preemployment physicals. In these unselected women the prevalence of hirsutism varied from 2 to 8% depending on the chosen cut-off Ferriman-Gallwey (F-G) score, with no significant difference between white and black women. Using an F-G score of 6 or more as indicative of hirsutism, 3.4% of blacks and 4.7% of whites had PCO, suggesting that PCO may be one of the most common reproductive endocrine disorders of women.

Azziz et al. (2004) determined the cumulative prevalence of PCOS in a population of 400 consecutive cases. They found a prevalence of 6.6% (26.5 of 400), including 15 subjects among the 347 women completing their evaluation and a calculated prevalence of 11.5 subjects among the remainder. The prevalence rates of PCOS for black and white women were 8.0 and 4.8%, respectively.

To determine the prevalence of PCO in the Greek population as well as associated metabolic parameters, Diamanti-Kandarakis et al. (1999) performed a cross-sectional study of 192 women of reproductive age (17 to 45 years) living on the Greek island of Lesbos. Subjects were divided into 4 groups according to the presence of hirsutism (defined as a Ferriman-Gallwey score of at least 6) and oligomenorrhea: group N (108 women), regular menses and absence of hirsutism; group 1 (56 women), regular menses and hirsutism; group 2 (10 women), oligomenorrhea and absence of hirsutism; and group 3 (18 women), oligomenorrhea and hirsutism. Body mass index (BMI), waist-to-hip ratio, and mean blood pressure did not differ among the studied groups. Hormonal profile was assessed by measuring free testosterone (FT). The prevalence of PCO, defined by the presence of oligomenorrhea and biochemical hyperandrogenism (FT at least 95th percentile of the normal women), was estimated to be 6.77% (13 of 192 women). Higher FT levels were observed in group 3 (oligomenorrhea and hirsutism) compared with groups N (P less than 0.00001) and 1 (P less than 0.0001) and in groups 1 (hirsutism) and 2 (oligomenorrhea) compared with group N (P less than 0.0001 and P less than 0.005, respectively). Sex hormone-binding globulin levels were lower in women with PCO and in groups 1 and 3 than those in group N (P less than 0.002, P less than 0.02, and P less than 0.002, respectively), independently of BMI. The metabolic profile was investigated by measurements of fasting glucose (FG), fasting insulin (FI), and estimation of the FG:I ratio. After covariance adjusted for the BMI, FI levels were higher in group 3 and in women with PCO than in normal (P less than 0.005 and P less than 0.002, respectively) and hirsute (P less than 0.05 and P less than 0.02, respectively) women, whereas FG levels did not differ among the studied groups. The FG:I ratio was lower in group 3, group 1, and in women with PCO than in normal women (P less than 0.05). The authors concluded that PCO appears to be a particularly common endocrine disorder in the Greek population studied and is associated with certain metabolic abnormalities. Their data suggested that the severity of the fasting hyperinsulinemia is associated with the severity of the clinical phenotype of hyperandrogenism independently of obesity.

Obiezu et al. (2001) presented evidence that women with PCOS have highly elevated urinary levels of PSA (176820) and kallikrein-2 (147960), and suggested these 2 serine proteases as promising markers of hyperandrogenism in females suffering from PCOS.

Gharani et al. (1997) presented linkage and association data indicating a strong relationship between the CYP11A1 (118485) locus and the polycystic ovary syndrome with hyperandrogenism.

Urbanek et al. (1999) tested 37 candidate genes for linkage and association with PCOS or hyperandrogenemia in 150 families. The strongest evidence for linkage was with the follistatin gene (136470), for which affected sisters showed increased identity by descent (72%). After correction for multiple testing, the follistatin findings were still highly significant. Although the linkage results for CYP11A1 were also nominally significant (P = 0.02), they were not significant after correction. In 11 candidate gene regions, at least 1 allele showed nominally significant evidence for population association with PCOS in the transmission/disequilibrium test. The strongest effect in this test was observed in the INSR (147670) region but was not significant after correction. Odunsi and Kidd (1999) pointed to the design of the study by Urbanek et al. (1999) and the clear presentation of the results as a model for studies of complex traits. Hyperandrogenemia was used in the study to define a 'homogeneous' subgroup of PCOS. They stated that the full-blown syndrome of hyperandrogenism, chronic anovulation, and polycystic ovaries affects up to 5 to 10% of all premenopausal women; other features may include obesity, hirsutism, and hyperinsulinism as well as increased risk for developing noninsulin-dependent diabetes mellitus (125853), atherosclerosis, hypertension, dyslipidemia, coronary artery disease, and endometrial carcinoma.

Gaasenbeek et al. (2004) reevaluated the relationship between CYP11A promoter variation and PCOS disease status and symptoms and serum testosterone levels. They genotyped a pair of CYP11A promoter microsatellites, including the pentanucleotide implicated in trait susceptibility (Gharani et al., 1997), in 371 PCOS patients of United Kingdom origin, using both case-control and family-based association methods, and in 1,589 women from a population-based birth cohort from Finland characterized for polycystic ovary symptomatology and testosterone levels. Although nominally significant differences in allele and genotype frequencies at both loci were observed in the United Kingdom case-control study, these findings were not substantiated in the other analyses, and no discernible relationship was seen between variation at these loci and serum testosterone levels. The authors concluded that the strength of, and indeed the existence of, associations between CYP11A promoter variation and androgen-related phenotypes had been substantially overestimated in previous studies.

Ehrmann et al. (2002) studied 212 women with PCOS (124 white of European ancestry, 57 African American, 13 Hispanic, 13 Asian American, and 5 Middle Eastern). Each subject was genotyped for 3 DNA polymorphisms in the CAPN10 gene (605286) associated with type II diabetes (SNP-43, -19, and -63). The white and African American subjects were examined for association of these polymorphisms with phenotypic features of PCOS and type II diabetes. Phenotypic traits in nondiabetic white probands did not differ whether analyzed for each individual SNP or haplotype combination, nor was there association of any SNP with any of the phenotypic features of type II diabetes or PCOS in nondiabetic African Americans. However, nondiabetic African Americans with the 112/121 haplotype combination had significantly higher insulin levels, in response to an oral glucose challenge, as reflected in the area under the insulin curve (257,021 +/- 95,384 vs 136,240 +/- 11,468 pmol/min; P = 0.03), compared with those with other haplotypes. This finding was particularly notable because the 112/121 subjects were less obese. In addition to its association with insulin levels in African Americans, the 112/121 haplotype combination was associated with an approximate 2-fold increase in risk of PCOS in both African Americans and whites.

Gonzalez et al. (2003) performed a haplotype-phenotype correlation study of CAPN10 haplotypes in 148 women showing ecographically detected polycystic ovaries combined with 1 or more clinical symptoms and in 93 unrelated controls. They reconstructed and analyzed 482 CAPN10 haplotypes in patients and controls. They confirmed an association of the SNP44 allele (605286.0004) with the PCO phenotype in the Spanish population (P = 0.02). In addition, they identified several CAPN10 alleles associated with phenotypic differences observed between PCO patients such as the presence of hypercholesterolemia or hyperandrogenic features or familial cancer incidence.

Tucci et al. (2001) studied 85 Caucasian PCO patients and 87 age-matched Caucasian control women for associations with 4 candidate genes: follistatin, CYP19 (107910), CYP17, and INSR. These genes were analyzed using microsatellite markers near or inside the genes. They found that only the INSR gene marker D19S884 was significantly associated with PCO. The INSR gene region was then fine-mapped with an additional panel of 9 markers, but only marker D19S884, located 1 cM telomeric to the INSR gene, was again associated with PCO. The authors concluded that a susceptibility gene for PCO is located on chromosome 19p13.3 in the INSR gene region.

Urbanek et al. (2005) tested for genetic linkage and association between PCOS and short tandem repeat polymorphisms in 367 families, by analysis of linkage and family-based association. They studied 367 families of predominantly European origin with at least one PCOS patient. Families included 107 affected sib (sister) pairs (ASPs) in 83 families, and 390 trios with both parents and an affected daughter. Linkage with PCOS was observed over a broad region of chromosome 19p13.2. The strongest evidence for association was observed with D19S884 (chi square = 11.85; nominal P less than 0.0006; permutation P = 0.034).

Urbanek et al. (2007) reported the sequence analysis and fine mapping of the chromosome 19p13.2 PCOS susceptibility locus and determined its impact on metabolic features of PCOS. They performed a family-based association study using DNA obtained from 1,723 individuals in 412 families with 412 index cases and 43 affected sisters, predominantly of European origin. Genotype-phenotype associations were assessed in 601 women with PCOS and 168 brothers of affected women. The D19S884 allele 8 (A8) in intron 55 of the FBN3 gene (608529) showed the strongest evidence for association with PCOS of 53 variants tested (P corrected = 0.0037). These findings strongly suggested that A8 of D19S884 accounts for the association of PCOS susceptibility at the chromosome 19p13.2 locus. The A8 allele was associated with higher fasting insulin levels and homeostasis model assessment for insulin resistance (HOMA-IR) in women with PCOS, independent of obesity; it was associated with higher levels of fasting proinsulin and proinsulin-to-insulin ratio (PIR) in brothers but was not associated with any metabolic profile in unaffected sisters.

San Millan et al. (2004) studied the possible association of PCOS with 15 genomic variants in 11 candidate genes previously described to influence insulin resistance, obesity, and/or type II diabetes mellitus in 72 PCOS patients and 42 healthy controls. Compared with controls, PCOS patients were more frequently homozygous for the -108T variant in paraoxonase (168820.0003) (36.6% vs 9.5%; P = 0.002) and homozygous for G alleles of the ApaI variant in IGF2 (147470) (62.9% vs 38.1%; P = 0.018). Paraoxonase is a serum antioxidant enzyme and, because -108T alleles result in decreased paraoxonase expression, this increase in oxidative stress might result in insulin resistance. G alleles of the ApaI variant in IGF2 may increase IGF2 expression, and IGF2 stimulates adrenal and ovarian androgen secretion.

The R453Q variant in the H6PD gene (138090.0002) and 83557insA mutation in the HSD11B1 gene (see 600713.0001) interact, resulting in cortisone reductase deficiency (CRD; 604931), a rare disorder characterized by a PCOS-like phenotype. San Millan et al. (2005) studied these mutations in PCOS in a total of 116 PCOS patients and 76 nonhyperandrogenic controls. Four controls and 5 patients presented 3 of 4 mutant alleles in H6PD R453Q and HSD11B1 83557insA, which is the genotype observed in some subjects with CRD. Estimates of 11-beta-HSD oxoreductase activity were measured in 6 of these 9 women, ruling out CRD. Patients homozygous for the R453 allele, which was more frequent in PCOS patients, presented with increased cortisol and 17-hydroxyprogesterone levels compared with carriers of Q453 alleles; these differences were not observed in controls. HSD11B1 83557insA genotypes were not associated with PCOS and did not influence any phenotypic variable.

Goodarzi et al. (2006) tested the hypothesis that haplotypes in the SRD5A1 (184753) and SRD5A2 (607306) genes are risk factors for PCOS and the severity of hirsutism in affected women. A total of 287 white women with PCOS and 187 controls participated. Haplotypes within both genes were associated with PCOS risk. The leu allele of the val89-to-leu variant in SRD5A2 was associated with protection against PCOS; this allele is known to modestly reduce 5-alpha-reductase activity. Haplotypes in SRD5A1 but not SRD5A2 were also associated with the degree of hirsutism in affected women. That only SRD5A1 haplotypes were associated with hirsutism suggested to Goodarzi et al. (2006) that only this isoform is important in the hair follicle.

Vink et al. (2006) studied the heritability of PCOS in a Dutch cohort. The resemblance in monozygotic twin sisters (tetrachoric correlation 0.71) for PCOS was about twice as large as in dizygotic twin and other sisters (tetrachoric correlation 0.38). The authors concluded that this study demonstrated a large influence of genetic factors to the pathogenesis of PCOS, justifying the search for susceptibility genes.

Goodarzi et al. (2007) studied whether variants in the SULT2A1 (125263) or STS (300747) genes are associated with dehydroepiandrosterone sulfate (DHEAS) levels in women with PCOS. In women with PCOS, rs182420 in SULT2A1 was associated with DHEAS levels (p = 0.0035), and 2 haplotypes carrying the minor allele of rs182420 were also associated with DHEAS levels (p = 0.04 each). Goodarzi et al. (2007) concluded that SULT2A1, but not STS, may play a role in the inherited adrenal androgen excess of PCOS.

Chen et al. (2011) conduced a genomewide association study of PCOS in Han Chinese. The discovery set included 744 PCOS cases and 895 controls; subsequent replications involved 2 independent cohorts (2,840 PCOS cases and 5,012 controls from northern Han Chinese; 498 cases and 780 controls from southern and central Han Chinese). Chen et al. (2011) identified strong evidence of association between PCOS and 3 loci: 2p16.3 (rs13405728; combined p value by metaanalysis P(meta) = 7.55 x 10(-21), OR = 0.71); 2p21 (rs13429458, P(meta) = 1.73 x 10(-23), OR = 0.67); and 9q33.3 (rs2479106, P(meta) = 8.12 x 10(-19), OR = 1.34).